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Background: Transpulmonary pressure is the effective pressure across the lung parenchyma and has been proposed as a guide for mechanical ventilation. The pleural pressure is challenging to directly measure in clinical setting and esophageal manometry using esophageal balloon catheters was suggested for estimation. However, the accuracy of using esophageal pressure to estimate pleural pressure is debated due to variability in the mechanical properties of respiratory system, esophagus and esophageal catheter. Furthermore, while a vertical pleural pressure gradient exists across lung regions, esophageal pressure balloon provides a single value, representing, at most, the pressure surrounding the esophagus., Methods: In a swine model with a preserved esophagus and a single homogenous, easily measurable intrathoracic pressure, we evaluated esophageal pressure's agreement with intrathoracic pressure at different positive end-expiratory pressure (PEEP) levels (0, 5, 10, 15 cmH 2 O). We assessed the improvement of measurement accuracy by correcting absolute esophageal values using a previously described technique, that accounts for the pressure generated by the esophageal wall in response to esophageal balloon inflation. The study involved five swine, wherein two different esophageal catheters were used alongside the four distinct PEEP levels. Swings, uncorrected and corrected absolute esophageal pressures (end-inspiratory, end-expiratory) were compared with their respective intrathoracic pressures. The effect of correction technique was assessed with manual incremental step inflation procedure., Results: We found that both catheters significantly overestimated absolute esophageal pressure compared to intrathoracic pressure (5.01 ± 3.32 and 6.06 ± 5.62 cmH 2 O at end-expiration and end-inspiration, respectively), with error increasing at higher positive end-expiratory pressure levels (end-expiration: 2.36 ± 2.03, 3.77 ± 1.37, 6.24 ± 2.51 and 7.69 ± 4.02 for each PEEP level, P < 0.0001; end-inspiration: 1.71 ± 2.10, 3.70 ± 1.73, 7.67 ± 3.62 and 11.14 ± 7.60 for each PEEP level, P = 0.0004). Applying the correction technique significantly improved agreement for absolute values (0.82 ± 1.62 and 1.86 ± 3.94 cmH 2 O at end-expiration and end-inspiration, respectively). Esophageal pressure swings accurately estimated intrathoracic pressure swings at low-medium intrathoracic pressures (-0.64 ± 0.62, -0.07 ± 0.53, 1.43 ± 1.51, and 3.45 ± 3.94 at PEEP 0, 5, 10 and 15 cmH 2 O, respectively; P = 0.0197)., Conclusions: The correction technique, based on the mechanical response of esophageal wall to the balloon inflation, is fundamental for obtaining reliable estimations of absolute intrathoracic pressure values, and for ensuring its correct application in clinical setting., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Italian Ministry of Health (permit number: 463/2018-PR, June 22, 2018), thus no specifical approval was required. Consent for publication Not applicable. Competing interests Dr. Pesenti reports personal fees from Baxter, Maquet, Boehringer Ingelheim and Xenios outside the submitted work. Dr. Grasselli reports personal fees from Maquet, Draeger, Pfizer, Thermo Fisher, MSD and Gilead outside the submitted work. Dr. Mojoli reports personal fees for lectures from GE Healthcare, Seda Spa, Hamilton Medical. The remaining authors have disclosed that they do not have any potential conflict of interest., (© 2024. The Author(s).)

Purpose: The novel coronavirus disease (COVID-19) has revived the debate on the optimal tidal volume during acute respiratory distress syndrome (ARDS). Some experts recommend 6 mL/kg of predicted body weight (PBW) for all patients, while others suggest 7-9 mL/kg PBW for those with compliance >50 mL/cmH 2 O. We investigated whether a tidal volume ≥ 7 ml/kg PBW may be safe in COVID-19 patients, particularly those with compliance >50 mL/cmH 2 O., Materials and Methods: This secondary analysis of a multicenter study compares the Intensive Care Unit (ICU) mortality among 600 patients ventilated with <7 or ≥ 7 mL/kg PBW. Compliance was categorized as <40, 40-50, or > 50 mL/cmH 2 O., Results: 346 patients were ventilated with <7 (6.2 ± 0.5) mL/kg PBW and 254 with ≥7 (7.9 ± 0.9) mL/kg PBW. ICU mortality was 33 % and 29 % in the two groups (p = 0.272). At multivariable regression analysis, tidal volume ≥ 7 mL/kg PBW was associated with lower ICU mortality in the overall population (odds ratio: 0.62 [95 %-confidence interval: 0.40-0.95]) and in each compliance category., Conclusions: A tidal volume ≥ 7 (up to 9) mL/kg PBW was associated with lower ICU mortality in these COVID-19 patients, including those with compliance <40 mL/cmH 2 O. This finding should be interpreted cautiously due to the retrospective study design., Trial Registration: ClinicalTrails.govNCT04388670., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Giacomo Grasselli and Alberto Zanella report financial support was provided by the Italian Ministry of Health (“Ricerca Corrente” funding to the Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico di Milano, Milan, Italy). The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

During COVID-19 pandemic, vaccination has been strongly recommended and advocated to prevent COVID-19 infection and adverse outcomes, particularly among at-risk populations. The vaccination against SARS-CoV-2 (COVAC) occurred at off-site locations capable of accommodating large crowds, distinct from the hospital setting, where a team of intensivists, emergency physicians, and nurses, ensuring prompt medical attention (medical occurrences, MO) in cases of adverse event following immunization. Our aims were to estimate the incidence of MO, and to assess its association with demographics, and vaccine characteristics. Our retrospective cohort study included all subject aged 12 years and older who received vaccinations at two large out-of-hospital vaccination hubs (Fiera Milano City, Palazzo delle Scintille), between April 12th and August 31st, 2021. Nine hundred and ninety-five thousand and twenty-eight vaccinations were administrated. MOs incidence rate was 278/100,000 doses (95% confidence interval (CI) 268-289). Most MOs were mild (86.27%) and mainly observed in subjects who received the Comirnaty vaccine; 92 MOs (3.32%) were severe and mostly occurred in recipients of the Vaxzeria vaccine. The incidence rate for hospital transfers following vaccination was 4.7/100,000 doses (95% CI 3.5-6.2) and any level of anaphylaxis occurred in 0.4 cases per 100,000 administrated doses (95% CI 0.3.-0.7). Sex, age, type of vaccine and first dose were associated with incidence of MO. Our results showed a low incidence rate in MOs after COVAC, mainly mild and support the feasibility, effectiveness and safety of vaccinations administered in hubs with a dedicated SEU located outside of the hospital setting., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Cell-free hemoglobin (CFH) is used to detect hemolysis and was recently suggested to trigger acute lung injury. However, its role has not been elucidated in severe acute respiratory distress syndrome (ARDS) patients undergoing extracorporeal membrane oxygenation (ECMO). We investigated the association of carboxyhemoglobin (COHb) and haptoglobin-two indirect markers of hemolysis-with mortality in critically ill patients undergoing veno-venous ECMO (VV-ECMO) with adjusted and longitudinal models (primary aim). Secondary aims included assessment of association between COHb and haptoglobin with the development of ventilator-associated pneumonia (VAP) and with hemodynamics. We retrospectively collected physiological, laboratory biomarkers, and outcome data in 147 patients undergoing VV-ECMO for severe ARDS. Forty-seven patients (32%) died in the intensive care unit (ICU). Average levels of COHb and haptoglobin were higher and lower, respectively, in patients who died. Higher haptoglobin was associated with lower pulmonary (PVR) and systemic vascular resistance, whereas higher COHb was associated with higher PVR. Carboxyhemoglobin was an independent predictor of VAP. Both haptoglobin and COHb independently predicted ICU mortality. In summary, indirect signs of hemolysis including COHb and haptoglobin are associated with modulation of vascular tone, VAP, and ICU mortality in respiratory ECMO. These findings suggest that CFH may be a mechanism of injury in this patient population., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.)

Purpose: This study aimed to investigate the effects of inspired oxygen fraction (FiO 2 ) and positive end-expiratory pressure (PEEP) on gas exchange in mechanically ventilated patients with COVID-19. Methods: Two FiO 2 (100%, 40%) were tested at 3 decreasing levels of PEEP (15, 10, and 5 cmH 2 O). At each FiO 2 and PEEP, gas exchange, respiratory mechanics, hemodynamics, and the distribution of ventilation and perfusion were assessed with electrical impedance tomography. The impact of FiO 2 on the intrapulmonary shunt (delta shunt) was analyzed as the difference between the calculated shunt at FiO 2 100% (shunt) and venous admixture at FiO 2 40% (venous admixture). Results: Fourteen patients were studied. Decreasing PEEP from 15 to 10 cmH 2 O did not change shunt (24 [21-28] vs 27 [24-29]%) or venous admixture (18 [15-26] vs 23 [18-34]%) while partial pressure of arterial oxygen (FiO 2 100%) was higher at PEEP 15 (262 [198-338] vs 256 [147-315] mmHg; P  < .05). Instead when PEEP was decreased from 10 to 5 cmH 2 O, shunt increased to 36 [30-39]% ( P  < .05) and venous admixture increased to 33 [30-43]% ( P  < .05) and partial pressure of arterial oxygen (100%) decreased to 109 [76-177] mmHg ( P  < .05). At PEEP 15, administration of 100% FiO 2 resulted in a shunt greater than venous admixture at 40% FiO 2, ((24 [21-28] vs 18 [15-26]%, P  = .005), delta shunt 5.5% (2.3-8.8)). Compared to PEEP 10, PEEP of 5 and 15 cmH 2 O resulted in decreased global and pixel-level compliance. Cardiac output at FiO 2 100% resulted higher at PEEP 5 (5.4 [4.4-6.5]) compared to PEEP 10 (4.8 [4.1-5.5], P  < .05) and PEEP 15 cmH 2 O (4.7 [4.5-5.4], P  < .05). Conclusion: In this study, PEEP of 15 cmH 2 O, despite resulting in the highest oxygenation, was associated with overdistension. PEEP of 5 cmH 2 O was associated with increased shunt and alveolar collapse. Administration of 100% FiO 2 was associated with an increase in intrapulmonary shunt in the setting of high PEEP. Trial registration: NCT05132933., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AMP reports personal fees from Baxter, Maquet, Boehringer Ingelheim, and Xenios outside the submitted work. GG reports consultation fees from Getinge, Draeger, Pfizer, Thermo Fisher, MSD, and Gilead. The remaining authors declare that they have no conflicts of interest.

Objectives: In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation (PSV) is a key objective when the patient's respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes., Design: Retrospective observational cohort study., Setting: Twenty-four Italian ICUs from February 2020 to May 2020., Patients: Mechanically ventilated ICU patients with COVID-19-induced respiratory failure., Intervention: The transition period from CMV to PSV was evaluated. We defined it as "failure of assisted breathing" if the patient returned to CMV within the first 72 hours., Measurements and Main Results: Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao 2 /Fio 2 ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99-1.00; p = 0.003). Patients in the success group displayed a better trend in Pao 2 /Fio 2 , Paco 2 , plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42-3.06; p < 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d; p < 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d, p = 0.04)., Conclusions: Our study emphasizes that the Pao 2 /Fio 2 ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Importance: Data on the association of COVID-19 vaccination with intensive care unit (ICU) admission and outcomes of patients with SARS-CoV-2-related pneumonia are scarce., Objective: To evaluate whether COVID-19 vaccination is associated with preventing ICU admission for COVID-19 pneumonia and to compare baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU., Design, Setting, and Participants: This retrospective cohort study on regional data sets reports: (1) daily number of administered vaccines and (2) data of all consecutive patients admitted to an ICU in Lombardy, Italy, from August 1 to December 15, 2021 (Delta variant predominant). Vaccinated patients received either mRNA vaccines (BNT162b2 or mRNA-1273) or adenoviral vector vaccines (ChAdOx1-S or Ad26.COV2). Incident rate ratios (IRRs) were computed from August 1, 2021, to January 31, 2022; ICU and baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU were analyzed from August 1 to December 15, 2021., Exposures: COVID-19 vaccination status (no vaccination, mRNA vaccine, adenoviral vector vaccine)., Main Outcomes and Measures: The incidence IRR of ICU admission was evaluated, comparing vaccinated people with unvaccinated, adjusted for age and sex. The baseline characteristics at ICU admission of vaccinated and unvaccinated patients were investigated. The association between vaccination status at ICU admission and mortality at ICU and hospital discharge were also studied, adjusting for possible confounders., Results: Among the 10 107 674 inhabitants of Lombardy, Italy, at the time of this study, the median [IQR] age was 48 [28-64] years and 5 154 914 (51.0%) were female. Of the 7 863 417 individuals who were vaccinated (median [IQR] age: 53 [33-68] years; 4 010 343 [51.4%] female), 6 251 417 (79.5%) received an mRNA vaccine, 550 439 (7.0%) received an adenoviral vector vaccine, and 1 061 561 (13.5%) received a mix of vaccines and 4 497 875 (57.2%) were boosted. Compared with unvaccinated people, IRR of individuals who received an mRNA vaccine within 120 days from the last dose was 0.03 (95% CI, 0.03-0.04; P < .001), whereas IRR of individuals who received an adenoviral vector vaccine after 120 days was 0.21 (95% CI, 0.19-0.24; P < .001). There were 553 patients admitted to an ICU for COVID-19 pneumonia during the study period: 139 patients (25.1%) were vaccinated and 414 (74.9%) were unvaccinated. Compared with unvaccinated patients, vaccinated patients were older (median [IQR]: 72 [66-76] vs 60 [51-69] years; P < .001), primarily male individuals (110 patients [79.1%] vs 252 patients [60.9%]; P < .001), with more comorbidities (median [IQR]: 2 [1-3] vs 0 [0-1] comorbidities; P < .001) and had higher ratio of arterial partial pressure of oxygen (Pao2) and fraction of inspiratory oxygen (FiO2) at ICU admission (median [IQR]: 138 [100-180] vs 120 [90-158] mm Hg; P = .007). Factors associated with ICU and hospital mortality were higher age, premorbid heart disease, lower Pao2/FiO2 at ICU admission, and female sex (this factor only for ICU mortality). ICU and hospital mortality were similar between vaccinated and unvaccinated patients., Conclusions and Relevance: In this cohort study, mRNA and adenoviral vector vaccines were associated with significantly lower risk of ICU admission for COVID-19 pneumonia. ICU and hospital mortality were not associated with vaccinated status. These findings suggest a substantial reduction of the risk of developing COVID-19-related severe acute respiratory failure requiring ICU admission among vaccinated people.

Veno-venous extracorporeal membrane oxygenation (vv-ECMO) represents one of the most advanced respiratory support for patients suffering from severe acute respiratory distress syndrome. During vv-ECMO a certain amount of extracorporeal oxygenated blood can flow back from the reinfusion into the drainage cannula without delivering oxygen to the patient. Detection and quantification of this dynamic phenomenon, defined recirculation, are critical to optimize the ECMO efficiency. Our study aimed to measure the recirculation fraction (RF) using a thermodilution technique. We built an in vitro circuit to simulate patients undergoing vv-ECMO (ECMO flow: 1.5, 3, and 4.5 L/min) with different cardiac output, using a recirculation bridge to achieve several known RFs (from 0% to 50%). The RF, computed as the ratio of the area under temperature-time curves (AUC) of the drainage and reinfusion, was significantly related to the set RF (AUC ratio (%) = 0.979 × RF (%) + 0.277%, p < 0.0001), but it was not dependent on tested ECMO and cardiac output values. A Bland-Altman analysis showed an AUC ratio bias (precision) of -0.21% for the overall data. Test-retest reliability showed an intraclass correlation coefficient of 0.993. This study proved the technical feasibility and computation validity of the applied thermodilution technique in computing vv-ECMO RF., Competing Interests: Disclosure: Prof. Grasselli reports personal fees from Getinge, Draeger, Fisher&Paykel, and Pfizer, outside the submitted work. Prof. Pesenti reports personal fees from Maquet, Novalung/Xenios, Baxter, and Boehringer Ingelheim, outside the submitted work. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Purpose: To evaluate the daily values and trends over time of relevant clinical, ventilatory and laboratory parameters during the intensive care unit (ICU) stay and their association with outcome in critically ill patients with coronavirus disease 19 (COVID-19)., Methods: In this retrospective-prospective multicentric study, we enrolled COVID-19 patients admitted to Italian ICUs from February 22 to May 31, 2020. Clinical data were daily recorded. The time course of 18 clinical parameters was evaluated by a polynomial maximum likelihood multilevel linear regression model, while a full joint modeling was fit to study the association with ICU outcome., Results: 1260 consecutive critically ill patients with COVID-19 admitted in 24 ICUs were enrolled. 78% were male with a median age of 63 [55-69] years. At ICU admission, the median ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO 2 /FiO 2 ) was 122 [89-175] mmHg. 79% of patients underwent invasive mechanical ventilation. The overall mortality was 34%. Both the daily values and trends of respiratory system compliance, PaO 2 /FiO 2 , driving pressure, arterial carbon dioxide partial pressure, creatinine, C-reactive protein, ferritin, neutrophil, neutrophil-lymphocyte ratio, and platelets were associated with survival, while for lactate, pH, bilirubin, lymphocyte, and urea only the daily values were associated with survival. The trends of PaO 2 /FiO 2 , respiratory system compliance, driving pressure, creatinine, ferritin, and C-reactive protein showed a higher association with survival compared to the daily values., Conclusion: Daily values or trends over time of parameters associated with acute organ dysfunction, acid-base derangement, coagulation impairment, or systemic inflammation were associated with patient survival., (© 2021. The Author(s).)

Patients with sepsis have typically reduced concentrations of hemoglobin and albumin, the major components of noncarbonic buffer power ( β ). This could expose patients to high pH variations during acid-base disorders. The objective of this study is to compare, in vitro, noncarbonic β of patients with sepsis with that of healthy volunteers, and evaluate its distinct components. Whole blood and isolated plasma of 18 patients with sepsis and 18 controls were equilibrated with different CO 2 mixtures. Blood gases, pH, and electrolytes were measured. Noncarbonic β and noncarbonic β due to variations in strong ion difference ( β SID ) were calculated for whole blood. Noncarbonic β and noncarbonic β normalized for albumin concentrations ( β NORM ) were calculated for isolated plasma. Representative values at pH = 7.40 were compared. Albumin proteoforms were evaluated via two-dimensional electrophoresis. Hemoglobin and albumin concentrations were significantly lower in patients with sepsis. Patients with sepsis had lower noncarbonic β both of whole blood (22.0 ± 1.9 vs. 31.6 ± 2.1 mmol/L, P < 0.01) and plasma (0.5 ± 1.0 vs. 3.7 ± 0.8 mmol/L, P < 0.01). Noncarbonic β SID was lower in patients (16.8 ± 1.9 vs. 24.4 ± 1.9 mmol/L, P < 0.01) and strongly correlated with hemoglobin concentration ( r  = 0.94, P < 0.01). Noncarbonic β Patients with sepsis are poorly protected against acute respiratory acid-base derangements due to a lower noncarbonic buffer power, which is caused both by a reduction in the major noncarbonic buffers, i.e. hemoglobin and albumin, and by a reduced buffering capacity of albumin. Electrolyte shifts from and to the red blood cells determining acute variations in strong ion difference are the major buffering mechanism during acute respiratory acid-base disorders.NORM was lower in patients [0.01 (-0.01 to 0.04) vs. 0.08 (0.06-0.09) mmol/g, P < 0.01]. Patients with sepsis and controls showed different amounts of albumin proteoforms. Patients with sepsis are exposed to higher pH variations for any given change in CO 2 due to lower concentrations of noncarbonic buffers and, possibly, an altered buffering function of albumin. In both patients with sepsis and healthy controls, electrolyte shifts are the major buffering mechanism during respiratory acid-base disorders. NEW & NOTEWORTHY Patients with sepsis are poorly protected against acute respiratory acid-base derangements due to a lower noncarbonic buffer power, which is caused both by a reduction in the major noncarbonic buffers, i.e. hemoglobin and albumin, and by a reduced buffering capacity of albumin. Electrolyte shifts from and to the red blood cells determining acute variations in strong ion difference are the major buffering mechanism during acute respiratory acid-base disorders.

During the COVID-19 pandemic, a shortage of mechanical ventilators was reported and ventilator sharing between patients was proposed as an ultimate solution. Two lung simulators were ventilated by one anesthesia machine connected through two respiratory circuits and T-pieces. Five different combinations of compliances (30-50 mL × cmH 2 O -1 ) and resistances (5-20 cmH 2 O × L -1 × s -1 ) were tested. The ventilation setting was: pressure-controlled ventilation, positive end-expiratory pressure 15 cmH 2 O, inspiratory pressure 10 cmH 2 O, respiratory rate 20 bpm. Pressures and flows from all the circuit sections have been recorded and analyzed. Simulated patients with equal compliance and resistance received similar ventilation. Compliance reduction from 50 to 30 mL × cmH 2 O -1 decreased the tidal volume (V T ) by 32% (418 ± 49 vs. 285 ± 17 mL). The resistance increase from 5 to 20 cmH 2 O × L -1 × s -1 decreased V T by 22% (425 ± 69 vs. 331 ± 51 mL). The maximal alveolar pressure was lower at higher compliance and resistance values and decreased linearly with the time constant (r² = 0.80, p < 0.001). The minimum alveolar pressure ranged from 15.5 ± 0.04 to 16.57 ± 0.04 cmH 2 O. Cross-flows between the simulated patients have been recorded in all the tested combinations, during both the inspiratory and expiratory phases. The simultaneous ventilation of two patients with one ventilator may be unable to match individual patient's needs and has a high risk of cross-interference.

Background: Bilateral lung transplantation results in pulmonary vagal denervation, which potentially alters respiratory drive, volume-feedback, and ventilatory pattern. We hypothesised that Neurally Adjusted Ventilatory Assist (NAVA) ventilation, which is driven by diaphragm electrical activity (EAdi), would reveal whether vagally mediated pulmonary-volume feedback is preserved in the early phases after bilateral lung transplantation., Methods: We prospectively studied bilateral lung transplant recipients within 48 h of surgery. Subjects were ventilated with NAVA and randomised to receive 3 ventilatory modes (baseline NAVA, 50%, and 150% of baseline NAVA values) and 2 PEEP levels (6 and 12 cm H 2 O). We recorded airway pressure, flow, and EAdi., Results: We studied 30 subjects (37% female; age: 37 (27-56) yr), of whom 19 (63%) had stable EAdi. The baseline NAVA level was 0.6 (0.2-1.0) cm H 2 O μV -1 . Tripling NAVA level increased the ventilatory peak pressure over PEEP by 6.3 (1.8), 7.6 (2.4), and 8.7 (3.2) cm H 2 O, at 50%, 100%, and 150% of baseline NAVA level, respectively (P<0.001). EAdi peak decreased by 10.1 (9.0), 9.5 (9.4) and 8.8 μV (8.7) (P<0.001), accompanied by small increases in tidal volume, 8.3 (3.0), 8.7 (3.6), and 8.9 (3.3) ml kg -1 donor's predicted body weight at 50%, 100%, and 150% of baseline NAVA levels, respectively (P<0.001). Doubling PEEP did not affect tidal volume., Conclusions: NAVA ventilation was feasible in the majority of patients during the early postoperative period after bilateral lung transplantation. Despite surgical vagotomy distal to the bronchial anastomoses, bilateral lung transplant recipients maintained an unmodified respiratory pattern in response to variations in ventilatory assistance and PEEP., Clinical Trial Registration: NCT03367221., Competing Interests: Declarations of interest GG reports personal fees from Draeger Medical, Getinge, Fisher & Paykel, Biotest, personal Thermofisher and personal fees from Getinge, all unrelated with the present work; TM reports personal fees from Drager, Fisher & Paykel, and Mindray, outside the submitted work; AP received personal fees from Maquet, Novalung/Xenios, Baxter and Boehringer Ingelheim, outside the present work. All other authors declare that they have no conflicts of interests., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Extracorporeal carbon dioxide removal (ECCO 2 R) is a promising strategy to manage acute respiratory failure. We hypothesized that ECCO 2 R could be enhanced by ventilating the membrane lung with a sodium hydroxide (NaOH) solution with high CO 2 absorbing capacity. A computed mathematical model was implemented to assess NaOH-CO 2 interactions. Subsequently, we compared NaOH infusion, named "alkaline liquid ventilation", to conventional oxygen sweeping flows. We built an extracorporeal circuit with two polypropylene membrane lungs, one to remove CO 2 and the other to maintain a constant PCO 2 (60 ± 2 mmHg). The circuit was primed with swine blood. Blood flow was 500 mL × min -1 . After testing the safety and feasibility of increasing concentrations of aqueous NaOH (up to 100 mmol × L -1 ), the CO 2 removal capacity of sweeping oxygen was compared to that of 100 mmol × L -1 NaOH. We performed six experiments to randomly test four sweep flows (100, 250, 500, 1000 mL × min -1 ) for each fluid plus 10 L × min -1 oxygen. Alkaline liquid ventilation proved to be feasible and safe. No damages or hemolysis were detected. NaOH showed higher CO 2 removal capacity compared to oxygen for flows up to 1 L × min -1 . However, the highest CO 2 extraction power exerted by NaOH was comparable to that of 10 L × min -1 oxygen. Further studies with dedicated devices are required to exploit potential clinical applications of alkaline liquid ventilation.

Background: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave., Methods: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020, in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19. Clinical data were collected on the day of ICU admission. Information regarding the use of prone position was collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Oxygen Responders if the PaO 2 /FiO 2 ratio increased ≥ 20 mmHg during prone position and as Carbon Dioxide Responders if the ventilatory ratio was reduced during prone position., Results: Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively, and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs. 33%, p < 0.001). Overall, prone position induced a significant increase in PaO 2 /FiO 2 ratio, while no change in respiratory system compliance or ventilatory ratio was observed. Seventy-eight % of the subset of 78 patients were Oxygen Responders. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p = 0.047). Forty-seven % of patients were defined as Carbon Dioxide Responders. These patients were older and had more comorbidities; however, no difference in terms of ICU mortality was observed (51% vs. 37%, p = 0.189 for Carbon Dioxide Responders and Non-Responders, respectively)., Conclusions: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching., Trial Registration: clinicaltrials.gov number: NCT04388670.

Objectives: Extracorporeal respiratory support, including low blood flow systems providing mainly extracorporeal CO2 removal, are increasingly applied in clinical practice. Gas exchange physiology during extracorporeal respiratory support is complex and differs between full extracorporeal membrane oxygenation and extracorporeal CO2 removal. Aim of the present article is to review pathophysiological aspects which are relevant for the understanding of hypoxemia development during extracorporeal CO2 removal. We will describe the mathematical and physiologic background underlying changes in respiratory quotient and alveolar oxygen tension during venovenous extracorporeal gas exchange and highlight the clinical implications., Design: Theoretical analysis of venovenous extracorporeal gas exchange., Setting: Italian university research hospital., Patients: None., Interventions: None., Measurements and Main Results: While the effect of extracorporeal CO2 removal on the respiratory quotient of the native lung has long been known, the role of extracorporeal oxygenation in dictating changes in the respiratory quotient has been less addressed. Indeed, both extracorporeal CO2 removal and extracorporeal oxygen delivery affect the respiratory quotient of the native lung and thus influence the alveolar PO2. Indeed, for the same amount of extracorporeal CO2 extraction, it is possible to reduce the FIO2, reduce the risk of absorption atelectasis, and maintain the same alveolar PO2, by increasing the extracorporeal oxygen delivery., Conclusions: Worsening of hypoxemia is frequent during low-flow extracorporeal CO2 removal combined with ultraprotective mechanical ventilation. In this context, increasing extracorporeal oxygen delivery, increases the respiratory quotient of the native lung and could reduce both the occurrence of alveolar hypoxia and absorption atelectasis, thus optimizing the residual lung function.

Importance: Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU)., Objective: To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy., Design, Setting, and Participants: This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020., Exposures: Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission., Main Outcomes and Measures: Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression., Results: Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (Fio2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29)., Conclusions and Relevance: In this retrospective cohort study of critically ill patients admitted to ICUs in Lombardy, Italy, with laboratory-confirmed COVID-19, most patients required IMV. The mortality rate and absolute mortality were high.

In patients undergoing extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS), it is unknown which clinical physiologic variables should be monitored to follow the evolution of lung injury and extrapulmonary organ dysfunction and to differentiate patients according to their course. We analyzed the time-course of prospectively collected clinical physiologic variables in 83 consecutive ARDS patients undergoing ECMO at a single referral center. Selected variables-including ventilator settings, respiratory system compliance, intrapulmonary shunt, arterial blood gases, central hemodynamics, and sequential organ failure assessment (SOFA) score-were compared according to outcome at time-points corresponding to 0%, 25%, 50%, 75%, and 100% of the entire ECMO duration and daily during the first 7 days. A logistic regression analysis was performed to identify changes between ECMO start and end that independently predicted hospital mortality. Tidal volume, intrapulmonary shunt, arterial lactate, and SOFA score differentiated survivors and nonsurvivors early during the first 7 days and over the entire ECMO duration. Respiratory system compliance, PaO2/FiO2 ratio, arterial pH, and mean pulmonary arterial pressure showed distinct temporal course according to outcome over the entire ECMO duration. Lack of improvement of SOFA score independently predicted hospital mortality. In ARDS patients on ECMO, temporal trends of specific physiologic parameters differentiate survivors from non-survivors and could be used to monitor the evolution of lung injury. Progressive worsening of extrapulmonary organ dysfunction is associated with worse outcome.

Purpose of Review: Extracorporeal support allows ultraprotective controlled and assisted ventilation, which can prevent lung and diaphragm injury. We focused on most recent findings in the application of extracorporeal support to achieve lung protection and diaphragm- protection, as well as on relevant monitoring., Recent Findings: A recent randomized trial comparing the efficacy of extracorporeal support as a rescue therapy to conventional protective mechanical ventilation was stopped for futility but post hoc analyses suggested that extracorporeal support is beneficial for patients with very severe acute respiratory distress syndrome. However, the optimal ventilation settings during extracorporeal support are still debated. It is conceivable that they should enable the highest amount of CO2 removal with lowest mechanical power.Extracorporeal CO2 removal can minimize acidosis and enable the use of ultra-protective lung ventilation strategies when hypoxemia is not a major issue. Moreover, it can protect lung and diaphragm function during assisted ventilation through control of the respiratory effort.Lung mechanics, gas exchange, diaphragm electrical activity, ultrasound, electrical impedance tomography could be integrated into clinical management to define lung and diaphragm protection and guide personalized ventilation settings., Summary: Technological improvement and the latest evidence indicate that extracorporeal support may be an effective tool for lung and diaphragm protection.

The ROX (Respiratory rate-OXygenation) index is an early predictor of failure of nasal high flow (NHF), with lower values indicating higher risk of intubation. We measured the ROX index at set flow rate of 30 and 60 l/min in 57 hypoxemic patients on NHF. Patients with increased ROX index values at higher flow (n = 40) showed worse baseline oxygenation, higher respiratory rate and lower ROX index in comparison to patients with unchanged or decreased ROX index values (n = 17). The ROX index variation between flows was correlated with the change in end expiratory lung volume. Set flow rate during NHF might impact the ROX index value., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Endotracheal suctioning is mandatory to prevent complications caused by the retention of tracheal secretions. Endotracheal suctioning is often performed late, when patients show signs of respiratory and hemodynamic alterations. We conceived a prototype device that, when synchronized with the ventilator, automatically removes secretions collected below the endotracheal tube (ETT) cuff, thus avoiding endotracheal suctioning. The aim of our investigation was to assess the performance of this novel prototype in vitro., Methods: Three studies were performed to examine the characteristics of the prototype. We tested device's ability to generate an effective artificial cough flow (artificial cough maneuver) > 1 L/s by rapidly deflating the ETT cuff within the time of a sustained inflation (at 30 and at 40 cm H 2 O) (cough flow study). We also tested the prototype's ability to remove the fluid positioned below the ETT cuff using saline dye (fluid removal study), and to prevent the aspiration of saline dye from above the ETT cuff during the deflation phase of the ETT cuff (aspiration study). The trachea model was positioned at 45° in the aspiration study, and horizontally in the other two studies., Results: In the cough flow study, the prototype provided an effective artificial cough maneuver, with a mean ± SD of 1.78 ± 0.19 L/s (range, 1.42-2.14 L/s). The tracheal pressure after ETT cuff deflation never decreased below the PEEP level. In the fluid removal study, the prototype cleared the fluid from below the ETT cuff and the experimental trachea. No fluid was aspirated from the area above the ETT cuff toward the lower airways., Conclusions: We conceived an system capable of automatically expelling fluid from below the ETT cuff outside an experimental trachea by generating an artificial cough maneuver. This system may decrease the use of endotracheal suctioning and its complications. Future in vivo studies are needed to confirm this first in vitro evaluation., (Copyright © 2019 by Daedalus Enterprises.)

Background: The high-flow nasal cannula (HFNC) delivers up to 60 l/min of humidified air/oxygen blend at a temperature close to that of the human body. In this study, we tested whether higher temperature and flow decrease patient comfort. In more severe patients, instead, we hypothesized that higher flow might be associated with improved comfort., Methods: A prospective, randomized, cross-over study was performed on 40 acute hypoxemic respiratory failure (AHRF) patients (PaO 2 /FiO 2  ≤ 300 + pulmonary infiltrates + exclusion of cardiogenic edema) supported by HFNC. The primary outcome was the assessment of patient comfort during HFNC delivery at increasing flow and temperature. Two flows (30 and 60 l/min), each combined with two temperatures (31 and 37 °C), were randomly applied for 20 min (four steps per patient), leaving clinical FiO 2 unchanged. Toward the end of each step, the following were recorded: comfort by Visual Numerical Scale ranging between 1 (extreme discomfort) and 5 (very comfortable), together with respiratory parameters. A subgroup of more severe patients was defined by clinical FiO 2  ≥ 45%., Results: Patient comfort was reported as significantly higher during steps at the lower temperature (31 °C) in comparison to 37 °C, with the HFNC set at both 30 and 60 l/min (p < 0.0001). Higher flow, however, was not associated with poorer comfort. In the subgroup of patients with clinical FiO 2  ≥ 45%, both lower temperature (31 °C) and higher HFNC flow (60 l/min) led to higher comfort (p < 0.01)., Conclusions: HFNC temperature seems to significantly impact the comfort of AHRF patients: for equal flow, lower temperature could be more comfortable. Higher flow does not decrease patient comfort; at variance, it improves comfort in the more severely hypoxemic patient.

The main target of extracorporeal support is to achieve viable gas exchange, while minimizing the risk of ventilator-induced lung injury, achieved through a decreased mechanical ventilation load on the natural lung. However, during veno-venous extracorporeal membrane oxygenation (ECMO), mechanical ventilation is still necessary in order to prevent lung collapse and/or if extracorporeal blood flow is not sufficient to guarantee adequate gas exchange. In this review, we will summarize the physiology of extracorporeal support and the rationale for continuing mechanical ventilation in this context. Furthermore, we will review the current clinical practice among ECMO centers and their suggestions regarding mechanical ventilator settings. While optimal ventilatory settings are still a matter of debate, the use of a strategy combining low tidal volume and limited inspiratory pressures is accepted worldwide. On the contrary, the choice of applied positive end-expiratory pressure (PEEP) varies between the total rest strategy and open lung strategy. Finally, the use of assisted or spontaneous ventilation will be discussed.

Purpose: Limited data exist on the correlation between higher flow rates of high-flow nasal cannula (HFNC) and its physiologic effects in patients with acute hypoxemic respiratory failure (AHRF). We assessed the effects of HFNC delivered at increasing flow rate on inspiratory effort, work of breathing, minute ventilation, lung volumes, dynamic compliance and oxygenation in AHRF patients., Methods: A prospective randomized cross-over study was performed in non-intubated patients with patients AHRF and a PaO 2 /FiO 2 (arterial partial pressure of oxygen/fraction of inspired oxygen) ratio of ≤300 mmHg. A standard non-occlusive facial mask and HFNC at different flow rates (30, 45 and 60 l/min) were randomly applied, while maintaining constant FiO 2 (20 min/step). At the end of each phase, we measured arterial blood gases, inspiratory effort, based on swings in esophageal pressure (ΔPes) and on the esophageal pressure-time product (PTP Pes ), and lung volume, by electrical impedance tomography., Results: Seventeen patients with AHRF were enrolled in the study. At increasing flow rate, HFNC reduced ΔPes (p < 0.001) and PTP Pes (p < 0.001), while end-expiratory lung volume (ΔEELV), tidal volume to ΔPes ratio (V T /ΔPes, which corresponds to dynamic lung compliance) and oxygenation improved (p < 0.01 for all factors). Higher HFNC flow rate also progressively reduced minute ventilation (p < 0.05) without any change in arterial CO 2 tension (p = 0.909). The decrease in ΔPes, PTP Pes and minute ventilation at increasing flow rates was better described by exponential fitting, while ΔEELV, V T /ΔPes and oxygenation improved linearly., Conclusions: In this cohort of patients with AHRF, an increasing HFNC flow rate progressively decreased inspiratory effort and improved lung aeration, dynamic compliance and oxygenation. Most of the effect on inspiratory workload and CO 2 clearance was already obtained at the lowest flow rate.

Purpose: Open lung strategy during ARDS aims to decrease the ventilator-induced lung injury by minimizing the atelectrauma and stress/strain maldistribution. We aim to assess how much of the lung is opened and kept open within the limits of mechanical ventilation considered safe (i.e., plateau pressure 30 cmH 2 O, PEEP 15 cmH 2 O)., Methods: Prospective study from two university hospitals. Thirty-three ARDS patients (5 mild, 10 moderate, 9 severe without extracorporeal support, ECMO, and 9 severe with it) underwent two low-dose end-expiratory CT scans at PEEP 5 and 15 cmH 2 O and four end-inspiratory CT scans (from 19 to 40 cmH 2 O). Recruitment was defined as the fraction of lung tissue which regained inflation. The atelectrauma was estimated as the difference between the intratidal tissue collapse at 5 and 15 cmH 2 O PEEP. Lung ventilation inhomogeneities were estimated as the ratio of inflation between neighboring lung units., Results: The lung tissue which is opened between 30 and 45 cmH 2 O (i.e., always closed at plateau 30 cmH 2 O) was 10 ± 29, 54 ± 86, 162 ± 92, and 185 ± 134 g in mild, moderate, and severe ARDS without and with ECMO, respectively (p < 0.05 mild versus severe without or with ECMO). The intratidal collapses were similar at PEEP 5 and 15 cmH 2 O (63 ± 26 vs 39 ± 32 g in mild ARDS, p = 0.23; 92 ± 53 vs 78 ± 142 g in moderate ARDS, p = 0.76; 110 ± 91 vs 89 ± 93, p = 0.57 in severe ARDS without ECMO; 135 ± 100 vs 104 ± 80, p = 0.32 in severe ARDS with ECMO). Increasing the applied airway pressure up to 45 cmH 2 O decreased the lung inhomogeneity slightly (but significantly) in mild and moderate ARDS, but not in severe ARDS., Conclusions: Data show that the prerequisites of the open lung strategy are not satisfied using PEEP up to 15 cmH 2 O and plateau pressure up to 30 cmH 2 O. For an effective open lung strategy, higher pressures are required. Therefore, risks of atelectrauma must be weighted versus risks of volutrauma., Trial Registration: Clinicaltrials.gov identifier: NCT01670747 ( www.clinicaltrials.gov ).

Purpose: To develop a mathematical model of oxygenation during venovenous extracorporeal membrane oxygenation (vv-ECMO)., Material and Methods: Total oxygen consumption, cardiac output, blood flow, recirculation, intrapulmonary shunt, hemoglobin, natural lung, and membrane lung oxygen fractions were chosen as inputs. Content, partial pressure, and hemoglobin saturation of oxygen in arterial, venous, pulmonary, and extracorporeal blood were outputs. To assess accuracy and predictive power of the model, we retrospectively analyzed data of 25 vv-ECMO patients. We compiled 2 software (with numerical, 2D and 3D graphical outputs) to study the impact of each variable on oxygenation., Results: The model showed high accuracy and predictive power. Raising blood flow and oxygen fraction to the membrane lung or reducing total oxygen consumption improves arterial and venous oxygenation, especially in severe cases; raising oxygen fraction to the natural lung improves oxygenation only in milder cases; raising hemoglobin always improves oxygenation, especially in the venous district; recirculation fraction severely impairs oxygenation. In severely ill patients, increasing cardiac output worsens arterial oxygenation but enhances venous oxygenation. Oxygen saturation of ECMO inlet is critical to evaluate the appropriateness of oxygen delivery., Conclusions: The model with the software can be a useful teaching tool and a valuable decision-making aid for the management of hypoxic patients supported by vv-ECMO., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: We hypothesized that the ventilator-related causes of lung injury may be unified in a single variable: the mechanical power. We assessed whether the mechanical power measured by the pressure-volume loops can be computed from its components: tidal volume (TV)/driving pressure (∆P aw), flow, positive end-expiratory pressure (PEEP), and respiratory rate (RR). If so, the relative contributions of each variable to the mechanical power can be estimated., Methods: We computed the mechanical power by multiplying each component of the equation of motion by the variation of volume and RR: [Formula: see text]where ∆V is the tidal volume, ELrs is the elastance of the respiratory system, I:E is the inspiratory-to-expiratory time ratio, and R aw is the airway resistance. In 30 patients with normal lungs and in 50 ARDS patients, mechanical power was computed via the power equation and measured from the dynamic pressure-volume curve at 5 and 15 cmH2O PEEP and 6, 8, 10, and 12 ml/kg TV. We then computed the effects of the individual component variables on the mechanical power., Results: Computed and measured mechanical powers were similar at 5 and 15 cmH2O PEEP both in normal subjects and in ARDS patients (slopes = 0.96, 1.06, 1.01, 1.12 respectively, R (2) > 0.96 and p < 0.0001 for all). The mechanical power increases exponentially with TV, ∆P aw, and flow (exponent = 2) as well as with RR (exponent = 1.4) and linearly with PEEP., Conclusions: The mechanical power equation may help estimate the contribution of the different ventilator-related causes of lung injury and of their variations. The equation can be easily implemented in every ventilator's software.

Background: Lung-protective ventilation strategy suggests the use of low tidal volume, depending on ideal body weight, and adequate levels of PEEP. However, reducing tidal volume according to ideal body weight does not always prevent overstress and overstrain. On the contrary, titrating mechanical ventilation on airway driving pressure, computed as airway pressure changes from PEEP to end-inspiratory plateau pressure, equivalent to the ratio between the tidal volume and compliance of respiratory system, should better reflect lung injury. However, possible changes in chest wall elastance could affect the reliability of airway driving pressure. The aim of this study was to evaluate if airway driving pressure could accurately predict lung stress (the pressure generated into the lung due to PEEP and tidal volume)., Methods: One hundred and fifty ARDS patients were enrolled. At 5 and 15 cmH2O of PEEP, lung stress, driving pressure, lung and chest wall elastance were measured., Results: The applied tidal volume (mL/kg of ideal body weight) was not related to lung gas volume (r (2) = 0.0005 p = 0.772). Patients were divided according to an airway driving pressure lower and equal/higher than 15 cmH2O (the lower and higher airway driving pressure groups). At both PEEP levels, the higher airway driving pressure group had a significantly higher lung stress, respiratory system and lung elastance compared to the lower airway driving pressure group. Airway driving pressure was significantly related to lung stress (r (2) = 0.581 p < 0.0001 and r (2) = 0.353 p < 0.0001 at 5 and 15 cmH2O of PEEP). For a lung stress of 24 and 26 cmH2O, the optimal cutoff value for the airway driving pressure were 15.0 cmH2O (ROC AUC 0.85, 95 % CI = 0.782-0.922); and 16.7 (ROC AUC 0.84, 95 % CI = 0.742-0.936)., Conclusions: Airway driving pressure can detect lung overstress with an acceptable accuracy. However, further studies are needed to establish if these limits could be used for ventilator settings.

Rationale: The assessment of lung recruitability in patients with acute respiratory distress syndrome (ARDS) may be important for planning recruitment maneuvers and setting positive end-expiratory pressure (PEEP)., Objectives: To determine whether lung recruitment measured by respiratory mechanics is comparable with lung recruitment measured by computed tomography (CT)., Methods: In 22 patients with ARDS, lung recruitment was assessed at 5 and 15 cm H2O PEEP by using respiratory mechanics-based methods: (1) increase in gas volume between two pressure-volume curves (P-Vrs curve); (2) increase in gas volume measured and predicted on the basis of expected end-expiratory lung volume and static compliance of the respiratory system (EELV-Cst,rs); as well as by CT scan: (3) decrease in noninflated lung tissue (CT [not inflated]); and (4) decrease in noninflated and poorly inflated tissue (CT [not + poorly inflated])., Measurements and Main Results: The P-Vrs curve recruitment was significantly higher than EELV-Cst,rs recruitment (423 ± 223 ml vs. 315 ± 201 ml; P < 0.001), but these measures were significantly related to each other (R(2) = 0.93; P < 0.001). CT (not inflated) recruitment was 77 ± 86 g and CT (not + poorly inflated) was 80 ± 67 g (P = 0.856), and these measures were also significantly related to each other (R(2) = 0.20; P = 0.04). Recruitment measured by respiratory mechanics was 54 ± 28% (P-Vrs curve) and 39 ± 25% (EELV-Cst,rs) of the gas volume at 5 cm H2O PEEP. Recruitment measured by CT scan was 5 ± 5% (CT [not inflated]) and 6 ± 6% (CT [not + poorly inflated]) of lung tissue., Conclusions: Respiratory mechanics and CT measure-under the same term, "recruitment"-two different entities. The respiratory mechanics-based methods include gas entering in already open pulmonary units that improve their mechanical properties at higher PEEP. Consequently, they can be used to assess the overall improvement of inflation. The CT scan measures the amount of collapsed tissue that regains inflation. Clinical trial registered with www.clinicaltrials.gov (NCT00759590).

Background: Obesity is associated in healthy subjects with a great reduction in functional residual capacity and with a stiffening of lung and chest wall elastance, which promote alveolar collapse and hypoxaemia. Likewise, obese patients with acute respiratory distress syndrome (ARDS) could present greater derangements of respiratory mechanics than patients of normal weight., Methods: One hundred and one ARDS patients were enrolled. Partitioned respiratory mechanics and gas exchange were measured at 5 and 15 cm H2O of PEEP with a tidal volume of 6-8 ml kg(-1) of predicted body weight. At 5 and 45 cm H2O of PEEP, two lung computed tomography scans were performed., Results: Patients were divided as follows according to BMI: normal weight (BMI≤25 kg m(-2)), overweight (BMI between 25 and 30 kg m(-2)), and obese (BMI>30 kg m(-2)). Obese, overweight, and normal-weight groups presented a similar lung elastance (median [interquartile range], respectively: 17.7 [14.2-24.8], 20.9 [16.1-30.2], and 20.5 [15.2-23.6] cm H2O litre(-1) at 5 cm H2O of PEEP and 19.3 [15.5-26.3], 21.1 [17.4-29.2], and 17.1 [13.4-20.4] cm H2O litre(-1) at 15 cm H2O of PEEP) and chest elastance (respectively: 4.9 [3.1-8.8], 5.9 [3.8-8.7], and 7.8 [3.9-9.8] cm H2O litre(-1) at 5 cm H2O of PEEP and 6.5 [4.5-9.6], 6.6 [4.2-9.2], and 4.9 [2.4-7.6] cm H2O litre(-1) at 15 cm H2O of PEEP). Lung recruitability was not affected by the body weight (15.6 [6.3-23.4], 15.7 [9.8-22.2], and 11.3 [6.2-15.6]% for normal-weight, overweight, and obese groups, respectively). Lung gas volume was significantly lower whereas total superimposed pressure was significantly higher in the obese compared with the normal-weight group (1148 [680-1815] vs 827 [686-1213] ml and 17.4 [15.8-19.3] vs 19.3 [18.6-21.7] cm H2O, respectively)., Conclusions: Obese ARDS patients do not present higher chest wall elastance and lung recruitability., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of the study was to determine the size and location of homogeneous inflamed/noninflamed and inhomogeneous inflamed/noninflamed lung compartments and their association with acute respiratory distress syndrome (ARDS) severity.In total, 20 ARDS patients underwent 5 and 45 cmH2O computed tomography (CT) scans to measure lung recruitability. [(18)F]2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) uptake and lung inhomogeneities were quantified with a positron emission tomography-CT scan at 10 cmH2O. We defined four compartments with normal/abnormal [(18)F]FDG uptake and lung homogeneity.The homogeneous compartment with normal [(18)F]FDG uptake was primarily composed of well-inflated tissue (80±16%), double-sized in nondependent lung (32±27% versus 16±17%, p<0.0001) and decreased in size from mild, moderate to severe ARDS (33±14%, 26±20% and 5±9% of the total lung volume, respectively, p=0.05). The homogeneous compartment with high [(18)F]FDG uptake was similarly distributed between the dependent and nondependent lung. The inhomogeneous compartment with normal [(18)F]FDG uptake represented 4% of the lung volume. The inhomogeneous compartment with high [(18)F]FDG uptake was preferentially located in the dependent lung (21±10% versus 12±10%, p<0.0001), mostly at the open/closed interfaces and related to recruitability (r(2)=0.53, p<0.001).The homogeneous lung compartment with normal inflation and [(18)F]FDG uptake decreases with ARDS severity, while the inhomogeneous poorly/not inflated compartment increases. Most of the lung inhomogeneities are inflamed. A minor fraction of healthy tissue remains in severe ARDS., (Copyright ©ERS 2016.)

Background: High tidal volume can cause ventilator-induced lung injury (VILI), but positive end-expiratory pressure (PEEP) is thought to be protective. We aimed to find the volumetric VILI threshold and see whether PEEP is protective per se or indirectly., Methods: In 76 pigs (22 ± 2 kg), we examined the lower and upper limits (30.9-59.7 mL/kg) of inspiratory capacity by computed tomography (CT) scan at 45 cmH2O pressure. The pigs underwent a 54-h mechanical ventilation with a global strain ((tidal volume (dynamic) + PEEP volume (static))/functional residual capacity) from 0.45 to 5.56. The dynamic strain ranged from 18 to 100 % of global strain. Twenty-nine pigs were ventilated with end-inspiratory volumes below the lower limit of inspiratory capacity (group "Below"), 38 within (group "Within"), and 9 above (group "Above"). VILI was defined as death and/or increased lung weight., Results: "Below" pigs did not develop VILI; "Within" pigs developed lung edema, and 52 % died before the end of the experiment. The amount of edema was significantly related to dynamic strain (edema 188-153 × dynamic strain, R (2) = 0.48, p < 0.0001). In the "Above" group, 66 % of the pigs rapidly died but lung weight did not increase significantly. In pigs ventilated with similar tidal volume adding PEEP significantly increased mortality., Conclusions: The threshold for VILI is the lower limit of inspiratory capacity. Below this threshold, VILI does not occur. Within these limits, severe/lethal VILI occurs depending on the dynamic component. Above inspiratory capacity stress at rupture may occur. In healthy lungs, PEEP is protective only if associated with a reduced tidal volume; otherwise, it has no effect or is harmful.

Background: During mechanical ventilation, stress and strain may be locally multiplied in an inhomogeneous lung. The authors investigated whether, in healthy lungs, during high pressure/volume ventilation, injury begins at the interface of naturally inhomogeneous structures as visceral pleura, bronchi, vessels, and alveoli. The authors wished also to characterize the nature of the lesions (collapse vs. consolidation)., Methods: Twelve piglets were ventilated with strain greater than 2.5 (tidal volume/end-expiratory lung volume) until whole lung edema developed. At least every 3 h, the authors acquired end-expiratory/end-inspiratory computed tomography scans to identify the site and the number of new lesions. Lung inhomogeneities and recruitability were quantified., Results: The first new densities developed after 8.4 ± 6.3 h (mean ± SD), and their number increased exponentially up to 15 ± 12 h. Afterward, they merged into full lung edema. A median of 61% (interquartile range, 57 to 76) of the lesions appeared in subpleural regions, 19% (interquartile range, 11 to 23) were peribronchial, and 19% (interquartile range, 6 to 25) were parenchymal (P < 0.0001). All the new densities were fully recruitable. Lung elastance and gas exchange deteriorated significantly after 18 ± 11 h, whereas lung edema developed after 20 ± 11 h., Conclusions: Most of the computed tomography scan new densities developed in nonhomogeneous lung regions. The damage in this model was primarily located in the interstitial space, causing alveolar collapse and consequent high recruitability.

Objectives: The Berlin definition of acute respiratory distress syndrome has introduced three classes of severity according to PaO2/FIO2 thresholds. The level of positive end-expiratory pressure applied may greatly affect PaO2/FIO2, thereby masking acute respiratory distress syndrome severity, which should reflect the underlying lung injury (lung edema and recruitability). We hypothesized that the assessment of acute respiratory distress syndrome severity at standardized low positive end-expiratory pressure may improve the association between the underlying lung injury, as detected by CT, and PaO2/FIO2-derived severity., Design: Retrospective analysis., Setting: Four university hospitals (Italy, Germany, and Chile)., Patients: One hundred forty-eight patients with acute lung injury or acute respiratory distress syndrome according to the American-European Consensus Conference criteria., Interventions: Patients underwent a three-step ventilator protocol (at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure). Whole-lung CT scans were obtained at 5 and 45 cm H2O airway pressure., Measurements and Main Results: Nine patients did not fulfill acute respiratory distress syndrome criteria of the novel Berlin definition. Patients were then classified according to PaO2/FIO2 assessed at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure. At clinical positive end-expiratory pressure (11±3 cm H2O), patients with severe acute respiratory distress syndrome had a greater lung tissue weight and recruitability than patients with mild or moderate acute respiratory distress syndrome (p<0.001). At 5 cm H2O, 54% of patients with mild acute respiratory distress syndrome at clinical positive end-expiratory pressure were reclassified to either moderate or severe acute respiratory distress syndrome. In these patients, lung recruitability and clinical positive end-expiratory pressure were higher than in patients who remained in the mild subgroup (p<0.05). When patients were classified at 5 cm H2O, but not at clinical or 15 cm H2O, lung recruitability linearly increases with acute respiratory distress syndrome severity (5% [2-12%] vs 12% [7-18%] vs 23% [12-30%], respectively, p<0.001). The potentially recruitable lung was the only CT-derived variable independently associated with ICU mortality (p=0.007)., Conclusions: The Berlin definition of acute respiratory distress syndrome assessed at 5 cm H2O allows a better evaluation of lung recruitability and edema than at higher positive end-expiratory pressure clinically set.

Purpose of Review: To compare the positive end-expiratory pressure selection aiming either to oxygenation or to the full lung opening., Recent Findings: Increasing positive end-expiratory pressure in patients with severe hypoxemia is associated with better outcome if the oxygenation response is greater and positive end-expiratory pressure tests may be performed in a few minutes. The oxygenation response to recruitment maneuvers was associated with better outcome in patients with acute respiratory distress syndrome from influenza A (H1N1). If, after recruitment maneuver, the recruitment is not sustained by sufficient positive end-expiratory pressure, the lung will unavoidably collapse. Several papers investigated the positive end-expiratory pressure selection according to the deflation limb of the pressure-volume curve. It is still questionable whether to consider oxygenation or respiratory mechanics change as the best marker for adequate selection. A growing interest is paid to the estimate of transpulmonary pressure, although no consensus is available on which methodology is preferable. Finally, the positive end-expiratory pressure adequate for full lung opening may be computed combining the computed tomography scan variables and the chest wall elastance., Summary: When compared, most of the methods give the same positive end-expiratory pressure values in patients with higher and lower recruitability. The positive end-expiratory pressure/inspiratory oxygen fraction tables are the only methods providing lower positive end-expiratory pressure in lower recruiters and higher positive end-expiratory pressure in higher recruiters.

Purpose: Partial pressure of carbon dioxide (PCO2), strong ion difference (SID), and total amount of weak acids independently regulate pH. When blood passes through an extracorporeal membrane lung, PCO2 decreases. Furthermore, changes in electrolytes, potentially affecting SID, were reported. We analyzed these phenomena according to Stewart's approach., Methods: Couples of measurements of blood entering (venous) and leaving (arterial) the extracorporeal membrane lung were analyzed in 20 patients. Changes in SID, PCO2, and pH were computed and pH variations in the absence of measured SID variations calculated., Results: Passing from venous to arterial blood, PCO2 was reduced (46.5 ± 7.7 vs 34.8 ± 7.4 mm Hg, P < .001), and hemoglobin saturation increased (78 ± 8 vs 100% ± 2%, P < .001). Chloride increased, and sodium decreased causing a reduction in SID (38.7 ± 5.0 vs 36.4 ± 5.1 mEq/L, P < .001). Analysis of quartiles of ∆PCO2 revealed progressive increases in chloride (P < .001), reductions in sodium (P < .001), and decreases in SID (P < .001), at constant hemoglobin saturation variation (P = .12). Actual pH variation was lower than pH variations in the absence of measured SID variations (0.09 ± 0.03 vs 0.12 ± 0.04, P < .001)., Conclusions: When PCO2 is reduced and oxygen added, several changes in electrolytes occur. These changes cause a PCO2-dependent SID reduction that, by acidifying plasma, limits pH correction caused by carbon dioxide removal. In this particular setting, PCO2 and SID are interdependent., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Evidence based medicine is an attempt to optimize the medical decision process through methods primarily based on evidence coming from meta-analyses, systematic reviews, and randomized controlled trials ("evidence-based medicine"), rather than on "clinical judgment" alone. The randomized trials are the cornerstones of this process. However, the randomized trials are just a method to prove or disprove a given hypothesis, which, in turn, derives from a general observation of the reality (premises or theories). In this paper we will examine some of the most recent randomized trials performed in Intensive Care, analyzing their premises, hypothesis and outcome. It is quite evident that when the premises are wrong or too vague the unavoidable consequences will be a negative outcome. We should pay when designing the trial an equal attention in defining premises and hypothesis that we pay for the trial conduction.

Background: It has been suggested that higher positive end-expiratory pressure (PEEP) should be used only in patients with higher lung recruitability. In this study, the authors investigated the relationship between the recruitability and the PEEP necessary to counteract the compressive forces leading to lung collapse., Methods: Fifty-one patients with acute respiratory distress syndrome (7 mild, 33 moderate, and 11 severe) were enrolled. Patients underwent whole-lung computed tomography (CT) scan at 5 and 45 cm H2O. Recruitability was measured as the amount of nonaerated tissue regaining inflation from 5 to 45 cm H2O. The compressive forces (superimposed pressure) were computed as the density times the sternum-vertebral height of the lung. CT-derived PEEP was computed as the sum of the transpulmonary pressure needed to overcome the maximal superimposed pressure and the pleural pressure needed to lift up the chest wall., Results: Maximal superimposed pressure ranged from 6 to 18 cm H2O, whereas CT-derived PEEP ranged from 7 to 28 cm H2O. Median recruitability was 15% of lung parenchyma (interquartile range, 7 to 21%). Maximal superimposed pressure was weakly related with lung recruitability (r = 0.11, P = 0.02), whereas CT-derived PEEP was unrelated with lung recruitability (r = 0.0003, P = 0.91). The maximal superimposed pressure was 12 ± 3, 12 ± 2, and 13 ± 1 cm H2O in mild, moderate, and severe acute respiratory distress syndrome, respectively, (P = 0.0533) with a corresponding CT-derived PEEP of 16 ± 5, 16 ± 5, and 18 ± 5 cm H2O (P = 0.48)., Conclusions: Lung recruitability and CT scan-derived PEEP are unrelated. To overcome the compressive forces and to lift up the thoracic cage, a similar PEEP level is required in higher and lower recruiters (16.8 ± 4 vs. 16.6 ± 5.6, P = 1).

We wish to report here a practical approach to an acute respiratory distress syndrome (ARDS) patient as devised by a group of intensivists with different expertise. The referral scenario is an intensive care unit of a Community Hospital with limited technology, where a young doctor, alone, must deal with this complicate syndrome during the night. The knowledge of pulse oximetry at room air and at 100% oxygen allows to estimate the PaO2 and the cause of hypoxemia, shunt vs. VA/Q maldistribution. The ARDS severity (mild [200

Objective: Positive end-expiratory pressure exerts its effects keeping open at end-expiration previously collapsed areas of the lung; consequently, higher positive end-expiratory pressure should be limited to patients with high recruitability. We aimed to determine which bedside method would provide positive end-expiratory pressure better related to lung recruitability., Design: Prospective study performed between 2008 and 2011., Setting: Two university hospitals (Italy and Germany)., Patients: Fifty-one patients with acute respiratory distress syndrome., Interventions: Whole lung CT scans were taken in static conditions at 5 and 45 cm H2O during an end-expiratory/end-inspiratory pause to measure lung recruitability. To select individual positive end-expiratory pressure, we applied bedside methods based on lung mechanics (ExPress, stress index), esophageal pressure, and oxygenation (higher positive end-expiratory pressure table of lung open ventilation study)., Measurements and Main Results: Patients were classified in mild, moderate and severe acute respiratory distress syndrome. Positive end-expiratory pressure levels selected by the ExPress, stress index, and absolute esophageal pressures methods were unrelated with lung recruitability, whereas positive end-expiratory pressure levels selected by the lung open ventilation method showed a weak relationship with lung recruitability (r = 0.29; p < 0.0001). When patients were classified according to the acute respiratory distress syndrome Berlin definition, the lung open ventilation method was the only one which gave lower positive end-expiratory pressure levels in mild and moderate acute respiratory distress syndrome compared with severe acute respiratory distress syndrome (8 ± 2 and 11 ± 3 cm H2O vs 15 ± 3 cm H2O; p < 0.05), whereas ExPress, stress index, and esophageal pressure methods gave similar positive end-expiratory pressure values in mild, moderate, and severe acute respiratory distress syndrome. The positive end-expiratory pressure selected by the different methods were unrelated to each other with the exception of the two methods based on lung mechanics (ExPress and stress index)., Conclusions: Bedside positive end-expiratory pressure selection methods based on lung mechanics or absolute esophageal pressures provide positive end-expiratory pressure levels unrelated to lung recruitability and similar in mild, moderate, and severe acute respiratory distress syndrome, whereas the oxygenation-based method provided positive end-expiratory pressure levels related with lung recruitability progressively increasing from mild to moderate and severe acute respiratory distress syndrome.

Rationale: Pressures and volumes needed to induce ventilator-induced lung injury in healthy lungs are far greater than those applied in diseased lungs. A possible explanation may be the presence of local inhomogeneities acting as pressure multipliers (stress raisers)., Objectives: To quantify lung inhomogeneities in patients with acute respiratory distress syndrome (ARDS)., Methods: Retrospective quantitative analysis of CT scan images of 148 patients with ARDS and 100 control subjects. An ideally homogeneous lung would have the same expansion in all regions; lung expansion was measured by CT scan as gas/tissue ratio and lung inhomogeneities were measured as lung regions with lower gas/tissue ratio than their neighboring lung regions. We defined as the extent of lung inhomogeneities the fraction of the lung showing an inflation ratio greater than 95th percentile of the control group (1.61)., Measurements and Main Results: The extent of lung inhomogeneities increased with the severity of ARDS (14 ± 5, 18 ± 8, and 23 ± 10% of lung volume in mild, moderate, and severe ARDS; P < 0.001) and correlated with the physiologic dead space (r(2) = 0.34; P < 0.0001). The application of positive end-expiratory pressure reduced the extent of lung inhomogeneities from 18 ± 8 to 12 ± 7% (P < 0.0001) going from 5 to 45 cm H2O airway pressure. Lung inhomogeneities were greater in nonsurvivor patients than in survivor patients (20 ± 9 vs. 17 ± 7% of lung volume; P = 0.01) and were the only CT scan variable independently associated with mortality at backward logistic regression., Conclusions: Lung inhomogeneities are associated with overall disease severity and mortality. Increasing the airway pressures decreased but did not abolish the extent of lung inhomogeneities.

In the prone position, computed tomography scan densities redistribute from dorsal to ventral as the dorsal region tends to reexpand while the ventral zone tends to collapse. Although gravitational influence is similar in both positions, dorsal recruitment usually prevails over ventral derecruitment, because of the need for the lung and its confining chest wall to conform to the same volume. The final result of proning is that the overall lung inflation is more homogeneous from dorsal to ventral than in the supine position, with more homogeneously distributed stress and strain. As the distribution of perfusion remains nearly constant in both postures, proning usually improves oxygenation. Animal experiments clearly show that prone positioning delays or prevents ventilation-induced lung injury, likely due in large part to more homogeneously distributed stress and strain. Over the last 15 years, five major trials have been conducted to compare the prone and supine positions in acute respiratory distress syndrome, regarding survival advantage. The sequence of trials enrolled patients who were progressively more hypoxemic; exposure to the prone position was extended from 8 to 17 hours/day, and lung-protective ventilation was more rigorously applied. Single-patient and meta-analyses drawing from the four major trials showed significant survival benefit in patients with PaO2/FiO2 lower than 100. The latest PROSEVA (Proning Severe ARDS Patients) trial confirmed these benefits in a formal randomized study. The bulk of data indicates that in severe acute respiratory distress syndrome, carefully performed prone positioning offers an absolute survival advantage of 10-17%, making this intervention highly recommended in this specific population subset.

In patients with acute respiratory distress syndrome (ARDS), in supine position, there is a decrease of inflation along the sternum vertebral axis, up to lung collapse. In 1991 we published a report showing that, in ARDS patients, shifting from supine to prone position led immediately to the inversion of the inflation gradient and to a redistribution of densities from dorsal to ventral lung regions. This led to a "sponge model" as a wet sponge, similar to a heavy edematous lung, squeezes out the gas in the most dependent regions, due to the weight-related increase of the compressive forces. The sponge model accounts for density distribution in prone position, for which the unloaded dorsal regions are recruited, while the loaded ventral region, collapses. In addition, the sponge model accounts for the mechanism through which the positive end-expiratory pressure acts as counterforce to oppose the collapsing, compressing forces. The final result of proning was that the inversion of gravitational forces, together with other factors such as lung-chest wall shape-matching and the heart weight led to a more homogeneous distribution of inflation throughout the lung parenchyma. This is associated with oxygenation improvement as the dorsal recruitment, for anatomical reasons, prevails on the ventral de-recruitment. The more homogeneous distribution of inflation (i.e. of stress and strain) decreases/prevents the ventilator-induced lung injury, as consistently shown in animal experiments. Finally, and a series of clinical trials led to the conclusion that in patients with severe ARDS, the prone position provides a significant survival advantage.

Purpose: To assess the time interval required to reach a new steady state of oxygenation-, ventilation-, respiratory mechanics- and hemodynamics-related variables after decreasing/increasing positive end expiratory pressure (PEEP)., Methods: In 23 patients (group 1) with acute respiratory distress syndrome (ARDS), PEEP was decreased from 10 to 5 cmH2O and, after 60', it was increased from 5 to 15 cmH2O. In 21 other ARDS patients (group 2), PEEP was increased from 10 to 15 cmH2O and, after 60', decreased from 15 to 5 cmH2O. Oxygenation, ventilation, respiratory mechanics and hemodynamic variables were recorded at time 5', 15', 30' and 60' after each PEEP change., Results: When PEEP was decreased, PaO2, PaO2/FiO2, venous admixture and arterial oxygen saturation reached their equilibrium after 5'. In contrast, when PEEP was increased, the equilibrium was not reached even after 60'. The ventilation-related variables did not change significantly with PEEP. The respiratory system compliance, when PEEP was decreased, significantly worsened only after 60'. Hemodynamics did not change significantly with PEEP. In the individual patients the change of oxygenation-related variables and of respiratory system compliance observed after 5' could predict the changes recorded after 60'. This was not possible for PaCO2., Conclusions: We could not find a unique equilibration time for all the considered variables. However, in general, a decremental PEEP test requires far lower equilibrium time than an incremental PEEP test, suggesting a different time course for derecruitment and recruitment patterns.

Introduction: Although computed tomography (CT) is widely used to investigate different pathologies, quantitative data from normal populations are scarce. Reference values may be useful to estimate the anatomical or physiological changes induced by various diseases., Methods: We analyzed 100 helical CT scans taken for clinical purposes and referred as nonpathological by the radiologist. Profiles were manually outlined on each CT scan slice and each voxel was classified according to its gas/tissue ratio. For regional analysis, the lungs were divided into 10 sterno-vertebral levels., Results: We studied 53 males and 47 females (age 64 ± 13 years); males had a greater total lung volume, lung gas volume and lung tissue. Noninflated tissue averaged 7 ± 4% of the total lung weight, poorly inflated tissue averaged 18 ± 3%, normally inflated tissue averaged 65 ± 8% and overinflated tissue averaged 11 ± 7%. We found a significant correlation between lung weight and subject's height (P <0.0001, r2 = 0.49); the total lung capacity in a supine position was 4,066 ± 1,190 ml, ~1,800 ml less than the predicted total lung capacity in a sitting position. Superimposed pressure averaged 2.6 ± 0.5 cmH2O., Conclusion: Subjects without lung disease present significant amounts of poorly inflated and overinflated tissue. Normal lung weight can be predicted from patient's height with reasonable confidence.

Assessment and monitoring of hemodynamics is a cornerstone in critically ill patients as hemodynamic alteration may become life-threatening in a few minutes. Defining normal values in critically ill patients is not easy, because 'normality' is usually referred to healthy subjects at rest. Defining 'adequate' hemodynamics is easier, which embeds whatever pressure and flow set is sufficient to maintain the aerobic metabolism. We will refer to the unifying hypothesis proposed by Schrier several years ago. Accordingly, the alteration of three independent variables - heart (contractility and rate), vascular tone and intravascular volume - may lead to underfilling of the arterial tree, associated with reduced (as during myocardial infarction or hemorrhage) or expanded (sepsis or cirrhosis) plasma volume. The underfilling is sensed by the arterial baroreceptors, which activate primarily the sympathetic nervous system and renin-angiotensin-aldosterone system, as well as vasopressin, to restore the arterial filling by increasing the vascular tone and retaining sodium and water. Under 'normal' conditions, therefore, the homeostatic system is not activated and water/sodium excretion, heart rate and oxygen extraction are in the range found in normal subjects. When arterial underfilling occurs, the mechanisms are activated (sodium and water retention) - associated with low central venous oxygen saturation (ScvO2) if underfilling is caused by low flow/hypovolemia, or with normal/high ScvO2 if associated with high flow/hypervolemia. Although the correction of hemodynamics should be towards the correction of the independent determinants, the usual therapy performed is volume infusion. An accepted target is ScvO2 >70%, although this ignores the arterial underfilling associated with volume expansion/high flow. For large-volume resuscitation the worst solution is normal saline solution (chloride load, strong ion difference = 0, acidosis). To avoid changes in acid-base equilibrium the strong ion difference of the infused solution should be equal to the baseline bicarbonate concentration.

Purpose of Review: To survey the causes of ventilator-induced lung injury focusing on its mechanical determinants, lung stress and strain., Recent Findings: Tidal volume per ideal body weight (tidal volume/IBW) and airway pressure (PAW) are poor surrogates of strain and stress, which are respectively defined as the ratio of volume variation to lung resting volume and transpulmonary pressure. In healthy lungs, ventilation becomes lethal with strain reaching total lung capacity (tidal volume/IBW around 30-40 ml/kg) and with its related stress (roughly 24 cmH2O). The striking discrepancy between experimental data and clinical scenarios (harm at tidal volume/IBW of 12 ml/kg) may be explained by lung dishomogeneity, locally generating 'stress risers' or 'pressure multipliers'. When mechanical ventilation becomes unsafe, as inferred from computed tomography-scan evaluation of dishomogeneity and stress/strain values, lung protective strategies can be maximized by further reducing tidal volume and increasing PAW (e.g. high frequency oscillatory ventilation). In alternative, artificial lungs may provide adequate gas exchange while reducing the load of mechanical ventilation. Recently, outcome benefit was shown with the use of this technique in H1N1 patients., Summary: When lung protective strategy is considered unsafe, various techniques of extracorporeal respiratory support may be applied, which by decreasing the load of mechanical ventilation, allow partial to total lung rest.

Purpose: Large infusion of crystalloids may induce acid-base alterations according to their strong ion difference ([SID]). We wanted to prove in vivo, at constant PCO(2), that if the [SID] of the infused crystalloid is equal to baseline plasma bicarbonate, the arterial pH remains unchanged, if lower it decreases, and if higher it increases., Methods: In 12 pigs, anesthetized and mechanically ventilated at PCO(2) ≈40 mmHg, 2.2 l of crystalloids with a [SID] similar to (lactated Ringer's 28.3 mEq/l), lower than (normal saline 0 mEq/l), and greater than (rehydrating III 55 mEq/l) baseline bicarbonate (29.22 ± 2.72 mEq/l) were infused for 120 min in randomized sequence. Four hours of wash-out were allowed between the infusions. Every 30 min up to minute 120 we measured blood gases, plasma electrolytes, urinary volume, pH, and electrolytes. Albumin, hemoglobin, and phosphates were measured at time 0 and 120 min., Results: Lactated Ringer's maintained arterial pH unchanged (from 7.47 ± 0.06 to 7.47 ± 0.03) despite a plasma dilution around 12%. Normal saline caused a reduction in pH (from 7.49 ± 0.03 to 7.42 ± 0.04) and rehydrating III induced an increase in pH (from 7.46 ± 0.05 to 7.49 ± 0.04). The kidney reacted to the infusion, minimizing the acid-base alterations, by increasing/decreasing the urinary anion gap, primarily by changing sodium and chloride concentrations. Lower urine volume after normal saline infusion was possibly due to its greater osmolarity and chloride concentration as compared to the other solutions., Conclusions: Results support the hypothesis that at constant PCO(2), pH changes are predictable from the difference between the [SID] of the infused solution and baseline plasma bicarbonate concentration.